This the genetic analysis of genes with presumed roles in mammalian development by making loss-of-function and gain-of-function mutations in mice. For example, I have collaborated with Daniel Sussman (University of Maryland School of Medicine) to study the mouse homologs of the Drosophila segment polarity gene dishevelled (dsh). dsh is required for target cells to respond to the wingless signal in Drosophila, by an unknown signal transduction mechanism. The mouse homologs for wingless, the Wnt family of genes, are involved in mouse development, since targeted disruptions of both Wnt-1 and Wnt-3a result in embryonic lethality. Two murine homologs for dsh have been isolated: dvl and dvl2. We are attempting to make null mutations of these two genes in mice, and we are overexpressing the dvl and Wnt genes in targeted areas of the mouse, particularly the limb bud. We will use mice with loss-of-function and gain-of-function mutations to dissect the Wnt/dvl signaling pathway in the mouse.